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MRA use does not limit empagliflozin benefit in HF with preserved ejection fraction

Journal of the American College of Cardiology
Reuters Health - 13/05/2022 - In patients with heart failure with preserved ejection fraction (HFpEF), empagliflozin reduced the combined primary endpoint of cardiovascular (CV) death and HF hospitalization regardless of background use of mineralocorticoid receptor antagonists (MRA), but its effectiveness at reducing HF hospitalizations was more pronounced in MRA nonusers, new data suggest.

The findings are from a subanalysis of the EMPEROR-Preserved study, in which patients with chronic HFpEF were randomly assigned to receive the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin or placebo, in addition to background medical therapy. Participants had EF >40%, elevated pro-brain natriuretic peptide (proBNP) and structural heart disease or documented hospitalization for heart failure in the past year. Overall, 91% of participants had hypertension, 86% were receiving beta blockers, and 52% had atrial fibrillation.

Previous evaluations of the use of MRAs in patients with HFpEF included subanalyses of the TOPCAT study, one of which suggested a benefit of spironolactone on CV mortality and HF hospitalizations. In another subgroup analysis, patients with EF <55% seemed to benefit from MRAs.

Given the possibility that background use of MRA in conjunction with an SGLT2 inhibitor might impact outcomes, Dr. Joao Ferreria of the Universidade do Porto, Porto, Portugal and colleagues analyzed the effect of the nonrandomized use of MRA by 37% of EMPEROR-Preserved participants.

Concomitant therapy varied between MRA users and nonusers, suggesting that MRA users were statistically a sicker patient population. Indeed, they had higher mean levels of proBNP (1,051 pg/ml versus 927 pg/ml) and higher rates of diabetes mellitus (51.2% versus 47.8%), LVEF <50% (41.2% versus 28.3%), Class III/IV HF (21.2% versus 16.7%), and loop diuretic use (77.9% versus 61.6%). The MRA group also had a smaller proportion with ACE/ARB use (77.5% versus 79.2%) and a higher proportion using angiotensin receptor-neprilysin inhibitors (ARNIs; 3.8% versus 1.3%).

Overall, rates of the primary combined outcome were lower in empagliflozin users vs the placebo group (6.86 vs 8.67 per 100 patient-years, HR 0.79, 95% CI 0.69-0.90).

While the benefit of empagliflozin was more pronounced in patients with no MRA use (HR 0.73, 95% CI 0.62-0.87) than in MRA users (HR 0.87, 95% CI 0.71-1.06), the difference was not statistically significant.

In the placebo group, rates of the combined primary endpoint were lower in MRA nonusers than in MRA users (8.2 versus 9.4 per 100 person-years, respectively).

In addition, total hospitalizations showed a statistical difference between MRA users (HR 0.60; 95% CI 0.47-0.75) versus nonusers (HR 0.90; 95% CI 0.68-1.19).

CV death reduction, which only trended in direction of SGLT2 inhibitor, was not different depending upon background MRA usage.

An ancillary benefit of empagliflozin was to significantly reduce the use of potassium binder or rates of investigator-reported hyperkalemia, particularly among MRA users. "SGLT2 inhibitors may prevent hyperkalemia, which may enable the use of MRAs in patients with HFpEF," the researchers said.

In an accompanying editorial, Dr. Marvin Konstam from Tufts University in Boston addressed the issue of differences in the benefit of SGLT2 inhibitors between MRA users and nonusers.

"There is no statistical evidence supporting a difference between MRA users and nonusers in incremental empagliflozin effect on the primary endpoint of combined morbidity and mortality," he wrote. "...In the absence of an SGLT2 inhibitor contraindication, such as Type 1 Diabetes or severe renal impairment, and given the relatively benign safety profile of these agents, the weight of evidence favors SGLT2 inhibitor use in both users and nonusers."

The impact of empagliflozin on reducing HF hospitalizations was seen in both users and nonusers of SGLT2 inhibitors with EF 41%-49% but was more pronounced in patients who were non-MRA users, in patients with EF >55%, and in patients with fluid overload as opposed to those who were euvolemic. The authors point out that in TOPCAT, the benefit of spironolactone was attenuated in EF >50-55%.

Fewer than 4% of participants in EMPEROR -Preserved were receiving ARNIs. Data is lacking on the incremental benefit in patients with HFmrEF of adding SGLT2 inhibitors or MRAs and instead of an ACE/ARB, as ARNI also showed incremental benefit in reduction of hospitalizations versus the ARB comparator valsartan in the PARAGON-HF trial in patients with EF up to 57%.

SOURCE: https://bit.ly/3FwSO7X and https://bit.ly/37AN2Wq Journal of the American College of Cardiology, online March 29, 2022.

By Austin Kutscher MD FACC

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